Bioactivation of nitroglycerin and vasomotor response to... : Hepatology (original) (raw)
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Bioactivation of nitroglycerin and vasomotor response to nitric oxide are impaired in cirrhotic rat livers
Dudenhoefer, Amy A.1, 2; Loureiro-Silva, Maurício R.1; Cadelina, Gregory W.1; Gupta, Tarun1; Groszmann, Roberto J.*,1
1From the Hepatic Hemodynamic Laboratory, VA Medical Center, West Haven; and Yale University School of Medicine, New Haven, CT
2Columbia University, New York, NY.
E-mail:[email protected]
*Address reprint requests to: Digestive Disease Section/111H, VA Healthcare System, 950 Campbell Ave., West Haven, CT 06516. fax: 203-933-3665.
Received July 06, 2001; Accepted May 16, 2002; previously published online December 30, 2003
Abstract
Nitroglycerin (NTG), a nitric oxide (NO) donor, has been shown to reduce portal pressure in cirrhotic patients. Using the in situ perfusion of normal and cirrhotic rat livers, we compared the vascular relaxation induced by either NTG or the spontaneous nitric oxide donor _S_-nitroso-_N_-acetylpenicillamine (SNAP). Normal and cirrhotic livers were perfused (40 mL/min, 37°C) with Krebs’ solution in a recirculating system. After preconstriction with methoxamine (10−4 mol/L), a dose-response study was performed using 6 cumulative doses of NTG or SNAP (10−7 to 3 × 10−5 mol/L). NOx (NO2− + NO3−) production in the perfusate was measured by chemiluminescence. Cirrhotic livers exhibited lower vasorelaxant responses, compared with normal livers, to both NTG (P < .0001) and SNAP (P = .0020). In normal livers, NTG and SNAP induced similar vasorelaxant responses (P = .44). In cirrhotic livers, NTG induced less vasorelaxation than SNAP (P < .0001). In the presence of NTG (P = .0045), but not SNAP (P = .99), NOx production in experiments with cirrhotic livers was lower than in experiments with normal livers. In conclusion, in cirrhotic rat livers, the vasorelaxant response to NTG is impaired owing to both a decreased metabolism of this NO donor and an inability of the hepatic vasculature to respond to NO.
Copyright © 2002 American Association for the Study of Liver Diseases.